Despite myriad challenges, clinicians see room for progress.
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Edited by Mark E. Davis, California Institute of Technology, Pasadena, CA, and approved March 3, 2016 (received for review November 8, 2015)
Article Figures & SI
Figures
- Fig. 1.
Preparation and physicochemical properties of the clustered nanoparticles. (A) Chemical structure of PCL-CDM-PAMAM/Pt. (B) Self-assembly and structural change of iCluster/Pt in response to tumor acidity and intracellular reductive environment. (C and E) DLS distributions of iCluster/Pt (C) and Cluster/Pt (E). (D and F) TEM images of iCluster/Pt (D) and Cluster/Pt (F) treated in PB at pH 6.8 for 0, 4, and 24 h, respectively. (Scale bar, 100 nm and for the Inset images, 50 nm.) (G and H) PAMAM (green line) and platinum drug (red line) release from iCluster (G) and Cluster (H) under three different conditions, which include PB at pH 7.4 to mimic a neutral environment, PB at pH 6.8 to mimic a tumor extracellular environment, and ascorbic acid solution (5 mM, pH 7.4) to mimic an intracellular redox environment. PAMAM release was quantified by HPLC, whereas platinum release was determined by ICP-MS.
- Fig. 2.
In vitro penetration and cell killing efficacy of clustered nanoparticles in BxPC-3 MCSs. (A) Penetration of RhBiClusterFlu and RhBClusterFlu in MCSs at pH 6.8 after a 4-h or 24-h incubation. The area marked with white circles was considered the inside area. (Scale bar, 200 μm.) (B) Mean fluorescence intensity (MFI) of green signals in the inside area of MCSs. (C) Quantification of fluorecein-positive MCS cells after incubation with different formulations at pH 6.8 for 4 h or 24 h. (D) Quantification of Pt content in MCSs after incubation with various formulations at pH 6.8 for 24 h. (E) Quantification of Pt content in DNA of MCS cells after various treatments at pH 6.8 for 24 h. (F) Apoptotic cells induced by different treatments at pH 6.8 for 24 h. All data are presented as mean ± SD (n = 3). *P < 0.05, ***P < 0.001.
- Fig. 3.
In vivo antitumor activity of iCluster/Pt in a BxPC-3 human pancreatic tumor model. (A) Pharmacokinetics of the formulations. These formulations were i.v. injected into ICR mice at a Pt dose of 60 µg per mouse. (B) Growth inhibition of BxPC-3 tumors by different treatments. Mice were i.v. administered at a Pt dose of 3 mg/kg on days 0, 2, and 4. ***P < 0.001. (C) Dose effect of iCluster/Pt on tumor growth inhibition. Mice were i.v. administered on days 0, 2, and 4. (D) Quantification of Pt content in tumor tissue. Formulations were administered i.v. at a Pt dose of 60 µg per mouse. Mice were killed at 12 h and 24 h postinjection, and tumors were excised. *P < 0.05, **P < 0.01. (E and F) Quantification of Pt content in tumor tissue cells (E) and GFP-positive tumor cells (F). For E and F, the tumor was established by s.c. injecting green fluorescent protein (GFP)-expressing BxPC-3 cells. At 12 h and 24 h after injection of the formulations, the tumors were excised, digested, and subjected to FACS to sort the total tumor cells and the GFP+ tumor cells. **P < 0.01, ***P < 0.001. Data are presented as mean ± SD n = 3 for A and D–F; n = 5 for B and C.
- Fig. 4.
Microdistribution of iCluster and Cluster in BxPC-3 xenograft tumor after i.v. injection. (A) CLSM images of immunofluorescence showing the microdistribution of RhBiClusterFlu and RhBClusterFlu in tumor tissue at 4 h postinjection. PAMAM was labeled with Flu (green), whereas the core of the nanoparticles was labeled with RhB (red), and blood vessels were marked with platelet endothelial cell adhesion molecule 1 (PECAM-1) and CFL-647 secondary antibody (yellow). (Scale bar, 50 μm.) (B) Real-time microdistribution of RhBiClusterFlu in BxPC-3 tumor at 10, 90, and 240 min postinjection. (Scale bar, 100 μm.) (C) Time and penetration depth-dependent distribution of RhBiClusterFlu. A region marked with the rectangular frame was selected for the analysis. The intensity profiles were obtained by normalizing the fluorescence intensity of each color to its initial intenstiy at 10 min.
- Fig. 5.
In vivo antitumor activity in drug-resistant and metastatic tumor models. (A) Inhibition of tumor growth of a A549R cisplatin-resistant human lung cancer model. Mice were i.v. administered an equivalent platinum dose of 1.5 mg/kg on days 0, 3, and 6. Data are presented as mean ± SD (n = 5). **P < 0.05, ***P < 0.001. (B) Kaplan–Meier plots of the animal survival in 4T1 tumor models (n = 10). Mice were treated at a platinum dose of 3 mg/kg via i.v. administration on days 10, 15, and 20 after tumor inoculation.
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Smart nanomedicine improves tumor penetration
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